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A protecting group-free synthesis of deazathiamine: a step toward inhibitor design.

ABSTRACT: The discovery of 3-deazathiamine diphosphate (deazaThDP) as a potent inhibitor analog of the cofactor thiamine diphosphate (ThDP) has highlighted the need for an efficient and scalable synthesis of deazaThDP. Such a method would facilitate development of analogs with the ability to inhibit individual ThDP-dependent enzymes selectively. Toward the goal of developing selective inhibitors of the mycobacterial enzyme 2-hydroxy-3-oxoadipate synthase (HOAS), we report an improved synthesis of deazaThDP without use of protecting groups. Tribromo-3-methylthiophene served as a versatile starting material whose selective functionalization permitted access to deazaThDP in five steps, with potential to make other analogs accessible in substantial amounts.

SUBMITTER: Zhao H

PROVIDER: S-EPMC2957563 | biostudies-literature | 2010 Nov

REPOSITORIES: biostudies-literature

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A protecting group-free synthesis of deazathiamine: a step toward inhibitor design.

Zhao Hong H de Carvalho Luiz Pedro S LP Nathan Carl C Ouerfelli Ouathek O

Bioorganic & medicinal chemistry letters 20100916 22

The discovery of 3-deazathiamine diphosphate (deazaThDP) as a potent inhibitor analog of the cofactor thiamine diphosphate (ThDP) has highlighted the need for an efficient and scalable synthesis of deazaThDP. Such a method would facilitate development of analogs with the ability to inhibit individual ThDP-dependent enzymes selectively. Toward the goal of developing selective inhibitors of the mycobacterial enzyme 2-hydroxy-3-oxoadipate synthase (HOAS), we report an improved synthesis of deazaThD ...[more]

PMID: 20943392

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